Michael Cooper on Calorie Restriction in Flies

Michael Cooper wrote to me to point out his research that suggests calorie restriction (CR) does not in fact work to extend life span in houseflies:

It is widely believed that CR extends life in all species. But, it does not. My work in Musca domestica (houseflies) reveals that CR does not extend their lifespan.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15319362

In fact this work raises questions about the claims in other species as well. For example: in drosophila [fruit flies], they claim significant effects of CR, but no one has been able to directly measure the food the flies consume, the amounts are simply too small. So instead, drosophila researchers use food dilution as a mimic for CR. I believe this tactic is used in other smaller species as well.

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FASEB J. 2004 Oct;18(13):1591-3. Epub 2004 Aug 19.
Effect of caloric restriction on life span of the housefly, Musca domestica.

Cooper TM, Mockett RJ, Sohal BH, Sohal RS, Orr WC.

Department of Biological Sciences, Southern Methodist University, Dallas, Texas 75275, USA.

Caloric restriction (CR) has been found to extend the life spans of a wide variety of species, transcending phylogenetic boundaries. The objective of this study was to test the generality of this phenomenon, using the male housefly as an insect model in which food intake can be quantified precisely. Sucrose was found to promote a longer life span than diets additionally containing proteins and lipids. Flies were fed sucrose or a more complex diet ad libitum (AL), or in amounts ranging from 50% to 100% of the average amount consumed by young flies. CR shortened rather than prolonged the life span of houseflies, particularly flies fed sucrose only. The rate of oxygen consumption was not affected by caloric restriction or by the exclusion of proteins and lipids from the diet, and the reproductive activity of male flies remained unchanged by sucrose feeding. Thus, it is unlikely that the life-shortening effects of CR can be explained either in terms of an adaptive response in metabolic rate or use of a suboptimal food source. Results of this study contradict the widely held view that CR has a life-extending effect in all species.
PMID: 15319362 [PubMed - in process]

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In the discussion section of this paper, the problem of inability to directly measure food intake in small species is addressed.

Reason, I work with both drosophila and houseflies. My major efforts are actually with drosophila. I do genetic engineering, molecular biology, with drosophila, trying to understand the aging process. So, I am intimately familiar with the care and feeding of this species.

In mice CR, the food is directly measured. As far as I know, all mammal studies have used direct measurement of food. It is in the small species that direct measurement becomes impractical. Houseflies may be close to the practical limit for direct measurement.

There are other more complicated ways of determining food intake, such as; radioactive or other means of labeling. So far as I know, these labeling methods have not been used in CR studies.

The plot thickens. There are certainly a number of studies indicating that fruit flies do experience the benefits of CR - but doubts raised over experimental methods would mean that a more rigorous examination of those findings is called for. On the other hand, if it were the case that fruit flies benefit from CR while houseflies do not ... well, that would seem to be a difference worth investigating more closely. Pinning down the biochemical and genetic roots of CR will have long term benefits for our health and longevity - hence all this careful work with flies.

Comments

Hi Reason & Fight Aging readers,

In my previous writing, I regret the use of "my work".

All authors on the FASEB paper contributed to this work.

All the authors, except me, are well-known and have contributed to the field of aging research in many different ways.

So, this Housefly CR effort is actually "our work".

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The implications of the housefly CR research are something that should be addressed.

It is intuitive to me that food dilution is not the same as calorie restriction. We may soon have data to support this.

Your statement:

"On the other hand, if it were the case that fruit flies benefit from CR while houseflies do not ... well, that would seem to be a difference
worth investigating more closely. Pinning down the biochemical and genetic roots of CR will have long term benefits for our health and longevity - hence all this careful work with flies."

Reason, I think you are right-on.

Obviously there are many things about CR that are not well understood. There is clearly a disconnect regarding CR in Houseflies and CR in Drosophila. The CR researchers working with Drosophila have important questions to consider.

I am continuing work in this area also.

Thanks Reason,
Mike

Posted by: Michael Cooper at November 16th, 2004 2:47 PM

Michael, quick question, since I only see the abstract.

I understand that you (a collective you I suppose) were able to directly measure food intake, thus ensuring an accurate measure of the degree of CR.

However, beyond that better system of control (relative to the Drosophila studies), I was wondering about other aspects of the experiment(s). At what stage was CR initiated, and was it a gradual decline in calories, or was it sudden-onset CR? I've seen studies in mice where CR did not benefit the mice, but the method of CR can sometimes be as critical as the presense of CR.

Also, one final point: Even if CR wasn't measured accurately in drosophila experiments, we at least know that *something* was increasing longevity in those experiments. So this doesn't invalidate the idea that something in diet is responsible, it only only casts doubt on the numerical correlation of degree of CR with longevity.

Posted by: Jay Fox at November 17th, 2004 7:59 AM

Interesting comments, Jay.

As you might expect, houseflies can be fed in separate containers; solid food and water.

CR was initiated on the fourth day after the flies eclosed (hatched). For some groups of flies the decline in available calories was gradual, for other groups not so gradual. The flies were restricted at 100%, 90%, 80%, 70%, 60% and 50% of average consumption, measured in the first four days. Fully-fed (ad libitum) flies were used as controls, this group had the longest mean survival time. The flies restricted at 50% died rather quickly, probably due to starvation. Other groups of flies had progressively shorter survival times as the severity of caloric restriction increased. Other experiments indicate that houseflies do not possess physiological mechanisms that permit adaptation to decreased calorie intake.

Experiments in houseflies were performed with widely varying diets to optimize survival time. So, yes, the diet does affect the lifespan of houseflies.

Typical feeding of Drosophila is such that they obtain everything, including water, from their semi-solid food mixture.

Food dilution changes the caloric density and nutrient composition of the food, relative to contol groups fed undiluted food. It is interesting that food dilution provides a positive CR-like effect in Drosophila.

Posted by: Michael Cooper at November 18th, 2004 6:07 PM

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